I am honored for the invitation to speak to you today on this very important issue. And although I am a registered nurse, I am here before you because of personal experiences as a patient undergoing superovulation during in vitro fertilization (IVF) attempts at several Boston fertility clinics over a decade ago - and because of what I’ve learned in the interim. My focus will be upon the adverse effects to the eggs, embryos, fetuses and women from one particular and commonly used drug, Lupron (leuprolide acetate), which is not FDA approved for fertility treatment; as well as addressing the risks from other fertility drugs and the assisted reproductive technology (ART) procedures in general.
For ease of reading and reference, this paper will be arranged under the following 13 headings:
1. Preliminary Comments

12. The Marginalization Of Victims And Lack Of Medico-legal Advocacy - p.40

13. A Request To Congress Asking For An Investigation Into Lupron and ART - p.44

(1) Preliminary Comments:

The drugs and fertility agents and the processes used in superovulation regimes for fertility treatments are exactly the same as that used to obtain women’s eggs for cloning research (although numerous variations of the protocols exist within the core group of ‘fertility drugs’). Cloning cannot take place without women’s eggs, and therefore the information I have to offer concerning the risks of fertility treatment have direct application to the process of therapeutic cloning. It has been estimated that some 8 million eggs per year may be necessary to sustain therapeutic cloning research -- how many women would that entail? My research into the medical literature revealed the maximum top three reports of numbers of eggs retrieved at one time as being: 91 eggs from one woman at one time (Source, ~1995), 71 eggs from one woman at one time (Lewit, 1995), and 56 eggs from one woman at one time (Lim, 1995). Since this research will require millions of eggs, this demand translates into the need to obtain as many eggs as possible from each woman per attempt. To quote from the consent form for egg donation for purposes of stem cell research at Advanced Cell Technology: “The idea is that the greater number of fully mature eggs, the greater the chance of successfully utilizing them in this research.” (ACT)
A dozen years ago, an article examined “[t]he risks associated with ovulation induction”, identifying that “epidemiologic studies are needed to determine the true risks associated with exposure” to the older, ‘traditional’ fertility drugs (St. Clair Stephenson, 1991). More than a decade later, the question is still being asked: ‘Are we ignoring potential dangers of in vitro fertilization and related treatments?’ (Winston, 2002). Costly complications from ART were, in part: a high incidence of first and second trimester bleeding, spontaneous abortion, toxemia, fetal growth restriction, anemia, anesthetic complications, ovarian hyperstimulation syndrome, culture medium infections (hepatitis and AIDS), visceral and vascular injuries, pathogenic infections, and breast and ovarian cancer. (Schenker, 1994). I believe it was Mirabella’s August 1993 issue which carried ‘A Doctor’s Story’, about a physician who took Clomid and was diagnosed with breast cancer. Large scale, epidemiological sound studies remain lacking on these earlier drugs, and yet in the interim years, the newer fertility ‘agents’ have been added and have themselves become ‘traditional’, standard, chemicals used in ovulation induction - but again, this standard has developed without any epidemiologically sound, long-term, safety data. It is noteworthy that while Lupron has become ‘standard’ within superovulation regimes, it is administered at various doses for various times, varying even within the various patients, and has varying effects.

There have been a number of past, as well as a flurry of recent, published reports of birth defects

in babies born from superovulation, IVF and other variants of ART, and it is widely acknowledged that critical long-term studies of the risks of ART are lacking (i.e., among others: Kola, 1988; Fischel, 1989; Saunders, 1989; Tanbo,1995; Silver, 1999; Aboulghar, 2001; Mitchell, 2002; BBC, 2002; Sutcliffe, 2002; Skloot, 2003). Titles often tell the story: “Ocular Manifestations in Children Born After In Vitro Fertilization’ (Anteby, 2001), ‘Congenital malformations in infants born after IVF: a population-based study’ (Ericson, 2001), ‘Hormone and Fertility Drug Use and the Risk of Neuroblastoma: A Report from the Children’s Cancer Group and the Pediatric Oncology Group’ (Olshan, 1999), ‘Congenital malformations in infants born after IVF: a population-based study’ (Ericson, 2001), ‘Brain worry over IVF children’ (Health, 2002), ‘Low and very low birth weight in infants conceived with use of assisted reproductive technology’ (Schieve, 2002), ‘The Risk of Major Birth Defects after Intracytoplasmic Sperm Injection and in Vitro Fertilization’ (Hansen, 2002), ‘In Vitro Fertilization May Be Linked To Bladder Defects’ (Trock, 2003), ‘Some Studies Sees Ills for In Vitro Children’ (Mestel, 2003), ‘Incidence of retinoblastoma in children born after in-vitro fertilisation’ (Moll, 2003). March 2002 brought headline news that the highly promoted and touted low incidence of birth defects from IVF (always stated as “similar to the general population, about 2-3%”) was now being reported as 9% - much higher than the general population. And now March 2003 brings news that IVF babies are at increased risk for urologic birth defects (Wood, 2003).

The American Society for Reproductive Medicine, in its Annual Meeting in 2002, released the following statement on October 14, 2002: “Studies Show Children of ART Develop Normally” (ASRM, 2002 - note link of ‘kidsareallright’). Figures don’t lie, but liars figure. (In 1990, the Federal Trade Commission brought complaints against 4 fertility providers for false claims in fertility treatment success rates [FTC, 1990]). To quote the New York Times: “Since the 1970's, fertility clinics have created almost a million children through experimental technologies. They’ve used untested and unregulated procedures ... Where is Washington in all of this?” (Skloot, 2003).

Online transcripts from the FDA’s Reproductive Health Drugs Advisory Committee Public Meeting, held October 18, 1999, identified “the need for pregnancy registries of babies born resulting from such [ART] treatment. These drugs include GnRH agonists and antagonists, human menopausal gonadotropins, purified urofillitropin, recombinant follicle stimulating, chorionic gonadotropin, and progesterone”. The United Kingdom recently announced plans to study 68,000 people born as a result of ART (Kaiser, 2002). Will the percentage of birth defects from ART continue to climb in the U.K., and the U.S., with further study? Do human embryos really need to be grown in human ovarian cancer cell lines (see Ben-Chetrit, 1996)? “Abnormal embryos” have been implanted into women (Munne, 1995) - what kind of consent did that experiment entail? One treatment, using intravenous immunoglobulin (IVIG), has raised questions about the “ability to screen for any diseases that could crop up 20 or 30 years down the road. Some doctors have even gone so far as to denounce [the] practice not as medicine, but witchcraft.” (Arnot, 2000).

Children have been born from co-culture with animal sera that could potentially contain prions, viruses, and/or unknown infectious agents - and my questions from the mid 1990's about risks from such co-cultures to embryos, children, and women went unanswered. In 2002, the FDA sent a ‘Dear Colleague’ letter, announcing that the transfer of such co-cultured embryos “constitute[d] a clinical investigation involving xenotransplantation” (Letter, 2002), but no enforcement action would be based on already existing embryos; and FDA and U.S. Public Health Service guidance documents recommend, among others, “follow patients for their lifetimes and counsel them to be alert to any unusual symptoms ... [and] they and their intimate contacts should defer from donation of blood and other tissues.” (CBER, 2002). Vero cells, from African green monkey kidney cells, have been used frequently in human embryo co-culture (i.e., see Veiga, 1999). In an online 1994 report of ART practices, it was stated that “[a]lthough the firm of Merieux refuses to accept any responsibility for the use of these [Vero] cells for the culture of human embryos, they are already widely used for this purpose by many specialists in medically assisted procreation ...” (Report, 1994). Who is minding this store?

The nation’s highest volume clinic was one of 10 participating clinics in a 1988 national study that attempted to look at the long-term health consequences of ART and drugs on the women and offspring - however the study made no mention of GnRHa’s - the results were touted as ‘reassuring’, yet results were inconclusive (although “warrant[ing] epidemiologic study”), and with too few study subjects (NICHHD, 1992). Of note, this writer, who developed multiple health problems, was a fertility patient at this clinic during this study - but was never asked to participate in this study. More significantly, another patient who was asked and did participate in this study (and shared her study documents with me) was subsequently dropped from the study following her hospitalization for severe ovarian hyperstimulation syndrome during her fertility treatment - in which she went into kidney failure and nearly died.
Many follow-up studies I’ve read of ART children do not identify the specific drugs received. My own experiences highlight the lack of informed consent that women experience when they “agree” to take fertility drugs. The best illustration of this is found in the Boston Globe’s quote of the Director from Boston IVF, the ‘nation’s largest volume fertility clinic’ (one of the two clinics I attended) who proclaimed “women do not need to know about the lack of FDA approval [of Lupron for fertility treatment]...” (Kong, 1996) Years later, this clinic would receive “$180,000 over two years to cover the cost of providing the embryos” “to Harvard University scientists for stem cell research. ... Harvard researchers plan to offer the new stem cells to any interested scientist at no cost, with no commercial restrictions. ...” (Mishra, 2001)
The profit within the fertility industry that exists today, as well as the hyped potential profit of therapeutic cloning tomorrow, along with lack of informed consent, the risks, and inherent exploitation all point to this issue having very serious ramifications upon many lives.

A recent Popular Science article unintentionally highlights the issue of consent: in the March 2003 series, the McNamara’s were featured as they had undergone experimental fertility treatment using cow uterus to grow their embryos. This Popular Science piece examined the risks of ART, and the McNamara’s conclusion at the end of this article was “Yeah, there is [a possibility of long-term effects] ... But ... we would still have done it.” (Skloot, 2003). However, Popular Science held a Popular Science Infertility Chat on America Online, and, in fact, the McNamara’s stated in the chat - after they had read the article - that “I think it’s important to point out that the information in the article wasn’t available when we made our decisions. .... Honestly, if it was presented in a way that it would cause trauma to our offspring, we probably wouldn’t have done it.” (Chat, 2003)
(2) Dead Women Don’t Talk:

Not until long after my fertility treatment did I learn that, before my treatment, there were questions raised and warning given regarding the fertility industry’s use of lack of informed consent, deceptive advertising and manipulated statistics. The first survey in the world of IVF clinics was done by two journalist/authors, Gena Corea and Susan Ince, and this survey revealed that while half of responding clinics had claimed high success rates, they had, in fact, produced not one baby (Corea, 1987). In 1992 I had begun legal action against my fertility treatment providers, and in 1997, Gena Corea (see also Corea, 1985) provided a statement to me intended for inclusion into the Offer of Proof for my medical malpractice tribunal (Millican v. Harvard Community Health Plan, Boston IVF, Natalie Schultz M.D., Brian Walsh M.D., Mahmood Niaraki M.D., Selwyn Oskowitz M.D., Michael Alper M.D.) The following 5 paragraphs are from that statement:

“... A lack of informed consent to IVF has been a constant and continuing problem with IVF from its earliest days when Lesley Brown, pregnant with the first IVF baby, Louise, was under the misapprehension that hundreds of such babies had already been born. She had no idea that she was in such an experimental program. ...”
“ ... The exact number of women who have died in in vitro fertilization programs is not known. However I have information on the deaths of ten women: in Germany, Brazil, Israel, Spain, and Martinique (in all these countries, I have tape-recorded interviews with the physicians and/or relatives of the dead women), and in Australia, New Zealand and Canada. Women entering IVF programs do not know of these deaths. Even physicians practicing IVF do not know of most of the deaths or their causes. With the exception of the Israelis, the IVF teams involved are not writing reports on the deaths for their professional publications nor are they delivering papers on the deaths at international meetings ... No professional or governmental organization is recording the deaths in a data bank.”
“Some Brazilians know of the first death -- of a woman named Zenaide Maria Bernardo, whose daughter and physician I interviewed in, respectively, Araraquara and Sao Paulo, Brazil. They know of her death because it occurred during a course on IVF for physicians and the course was a huge media event, covered by Globo, a national television station and the fourth largest in the world. The death could hardly be covered up when the television cameras were rolling. But aside from these Brazilian citizens, few in the public know of any IVF deaths.”

“To date, IVF deaths are known to have occurred due to hyperstimulation of the ovaries through the administration of hormones; anesthesia for laparoscopy; infection following laparoscopy; bleeding following laparoscopy; bleeding following ultrasonically-guided puncture of egg follicles; and ectopic pregnancy.”

“Physicians and the public relations firms hired by the IVF industry often give women the impression that IVF is a low-risk procedure. How do they know it is low-risk? I have interviewed physicians around the world on IVF deaths and without exception, I have known of, and had documentation on, more IVF deaths than any of them claimed to. Why is that? If scientists doing IVF do not know of the deaths their programs are causing, why don’t they? What are the mechanisms by which this information has been obscured? Through their journals and conferences, physicians share information on every slight change in drug protocol for inducing artificial ovulation. Shouldn’t information on deaths, injuries, psychotic breaks, lengthy recoveries also be shared? It’s not. ...”

(3) On The Count of Eggs and Money:
Early articles describe Lupron’s application in ovulation induction regimes as “in special situations” (Blankstein, 1988), yet Lupron “began to be widely used for IVF in 1989" (Martin, 1994). By 1990 fertility industry figures, GnRHa’s were utilized in 97% of reported assisted reproductive technology cycles (MRI, 1992), with Lupron identified as the “prevalent choice” and most frequently prescribed GnRHa in this country (Keenan, 1991; Martin, 1994). The fertility industry had already achieved the recognition of being more than a billion dollar industry by 1990 (Talan, 1990), and sounding like a trumpet, a 1991 publication proclaimed “Chronic indications for GnRH agonist therapy among IVF/GIFT patients are likely to increase significantly in the immediate future.” (Gordon, 1991). Early on, Lupron’s use had been described as increasing the use/purchase of Pergonal (manufactured by Serono) by 50% (Keenan, 1991), and it was known that “[t]he direct financial cost of cycles incorporating adjunctive leuprolide therapy was 40% greater than the cost of cycles in which no leuprolide therapy was used.” (Dodson, 1991). At this time, the failure rates for IVF were around 80 - 85%: “rarely has a technology that has had such dismal success rates been so quickly accepted.” (Raymond, 1993).

When I complained to my Harvard HMO about their use of this experimental drug, their response was an illustration in how definitions can easily be changed; they state that institutional review board (IRB) review was unnecessary because Lupron was not being used in “research”, but rather Lupron was being used in a “therapeutic” manner. The Office for Protection from Research Risks has received reports from major research institutions of “startling ignorance” of IRB policies regarding informed consent in reproductive research (Ellis, 1995).
Because of my nightmare experiences as a fertility consumer, I became involved in drafting a first in the nation bill which would have required fertility clinics to have a license to operate, and which would have mandated informed consent of ART risks (Millican (2), 1992; Lasalandra, 1995). My collaborator in drafting this bill, Linda DeBenedictis, had also attended Boston IVF and had also been mandated to switch to Lupron - and her story was told over a 3 part series on Boston TV news. Doctors from Boston IVF told the DeBenedictis’ that 3 eggs had fertilized and 3 embryos were ready for implantation the next morning. Upon arrival at the clinic the next morning, there were not 3 embryos for implantation - there were no embryos for implantation. The clinic maintained there had been an “error in communication”, and that no embryos had fertilized (WHDH, 1989).

From 1992 - 1999, I provided verbal and written testimony to the MA. Health Care Committee in support of this bill (MA. H. 3308), and these documents are a testament to my experiences, my learning curve, and the mounting evidence against Lupron. My 1992 written testimony states: “... nearly every IVF clinic has mandated that women take Lupron - or they will not be allowed to cycle ... Women are told that Lupron results in better quality and better quantity of eggs.” In 1995, my testimony states I was told that I “must use Lupron” if I wanted to undergo IVF. Women reported successful IVF births without Lupron, yet were made to use Lupron nonetheless, and reported subsequent failure in these switched cycles. Other women using Lupron complain of failure to suppress and canceled IVF cycles, premature leutinization, and poor quality eggs with Lupron (see Chetkowski, 1989; Schoolcraft, 1991). The internet posts of women identify the badgering, and coercion, and manipulation, and threats used to convince women into taking Lupron for a variety of indications - many refer to their doctor as trying to “shove it down [their] throat”.

Later I would learn that the first survey in the world of IVF clinics was conducted in 1986 (Raymond, 1993), revealing deceptive success rate claims and manipulated figures (Corea, 1987). As a result, the 101st Congress held hearings in the SubCommittee on Regulation, Business Opportunities, and Energy, House of Representatives, in which data from 191 fertility clinics was published. This clinic specific information shows a significant number of these reporting fertility clinics had recently “switched” and/or “began to use” Lupron in their superovulation regimes - without any IRB review (Hearing, 1989). One reporting clinic provided testimony identifying Lupron as “a costly, experimental medicine ...” (Kemmann, 1989).
One of the fertility clinics that I attended in 1990, Brigham & Womens, had as its protocol in its IVF brochure that “Lupron is only used in certain diagnosis”, but in 1991 this clinic changed its brochure to read “Lupron is widely prescribed”. I would later learn that the director of this IVF clinic, Dr. Andrew Friedman, had been a lead Lupron investigator, had received numerous grants and funds from Lupron’s manufacturer, Takeda Abbott Pharmaceuticals (TAP), and had published extensively on Lupron. Dr. Friedman was ultimately found guilty of falsifying and fabricating approximately 80% of the data in four Lupron studies, two of which had been published and were subsequently retracted. Friedman had “altered and fabricated information in patient medical records, falsified research notes by changing dates and changing and adding text”, and fabricated notes and fabricated patients for clinical visits that had not taken place. (Federal Register, 1996; see also Lasalandra, 1998; Millican, 1998; Kong, 1999).

My 1995 written testimony in support of MA. H 3308 identified “manipulated figures” in a fifth Friedman Lupron study (Millican, 1995). To the best of my knowledge, while confidential Harvard documents state further investigation into other Friedman Lupron data should be explored, no investigation has been conducted beyond the four, identified, fraudulent Friedman Lupron studies. Two years after the Federal Register publication of Friedman’s fraud, the MA. Board of Registration ‘acted’ by temporarily suspending his medical license, however the published and cited bogus data is irretrievable. And in fact, one fraudulent and retracted Friedman Lupron study was cited as a credible reference and data source in an article published on Medscape (Women’s Health) in August 2001 (Data, 2001). In a similar faux pas, FDA Consumer magazine recently had to provide a correction to an article in which it erroneously stated GnRHa’s would “shrink fibroids” - a statement told repeatedly to women despite the fact Lupron has only been approved for “the anemia associated with fibroids, when iron therapy alone has been ineffective”. The indication of Lupron’s use to “shrink fibroids” received the FDA’s rejection in the past, and no FDA approval has ever been granted for this indication. (FDA, 2002)

NBC Dateline did a story January 2, 2000 about severe side effects experienced by women taking Lupron for endometriosis (adverse events such as joint pain, numbness, memory loss, irregular heart beat, suicidal depression, whole body swelling, grand-mal seizures). Quoting from the Dateline story transcript: “[Dateline] asked TAP about the complaints of these women, given TAP’s marketing of Lupron as “perhaps making miracles possible.” While the company declined an on-camera interview, [Dateline] met with several top executives, who told [Dateline] the preponderance of evidence suggests that Lupron works, otherwise women wouldn’t continue to use it.” Dateline’s story concluded with “[Lupron] is also widely and routinely used for women going through fertility treatments.” (Dateline, 2000).